tbuckley/cabot-search huggingface dataset:
Abstract 3308: Predictive biomarkers of response to immune checkpoint inhibitors in metastatic renal cell carcinoma
Authors: Takanobu Motoshima, Yuji Miura, Toshiki Amami, Shigeyasu Kitano, Masaya Baba, Tomomi Kamba
Journal: Cancer Research (2023)

Abstract Background: Since the introduction of Immune checkpoint inhibitors (ICIs) combination therapy to renal cancer treatment, it has revolutionized the treatment of renal cancer, with many reports of excellent therapeutic effects. However, it is not known which patients will benefit the most. Materials and methods: PBMC(Peripheral Blood Mononuclear Cells)samples were collected prospectively from patients with advanced and metastatic renal cell carcinoma (RCC) prior to initiation of ICI treatment (baseline) and 2 or 3 weeks after the first cycle of ICI treatment (post-dose 1). We collected PBMCs from 24 patients with a cell count of more than 50,000 were analyzed using antibodies that distinguishCD4 and CD8 cells including Effector, Memory cells population, B cells, Monocyte, NK(Natural Killer) cells, MDSC(Myeloid-Derived Suppressor Cells ), DC(Dendritic cells), CD4 (Th1, Th2, Th17, Tfh), Immune checkpoint molecules including CD223 (LAG3), CD279 (PD1), TIM3, CD152 (CTLA4), CD278 (ICOS), FOXP3. Results: First, we compared the Fold Change (FC) before and after drug administration in the group that did not respond to treatment (SD: Stable Disease or PD: Progressive disease) and the group that did respond to treatment (PR: Partial Response, CR: Complete Response). The results showed that CD4 positive cells (non-responder Median 0.79 vs responder Median 1.64, p=0.0317, respectively), monocytes: CD56-HLADR+ (non-responder Median 0.87 vs responder Median 1.20, p=0.0159, respectively), but not in other cell populations.Next, we compared the groups that did and did not respond to treatment before and after treatment. We could not identify any biomarker cell population before treatment, the number of CD4 Effector cells (CD4+CD45RO-CD197-) was significantly higher in the post-treatment (PD1) group (PR or CR) than in the non-treatment group (SD or PD). (p=0.0303, respectively) Conclusion: Elevation of CD4 positive cells and monocytes (CD56-HLADR+) before and after treatment and the number of CD4 Effector cells (CD4+CD45RO-CD197-) after treatment may be biomarkers of treatment response. Citation Format: Takanobu Motoshima, Yuji Miura, Toshiki Amami, Shigeyasu Kitano, Masaya Baba, Tomomi Kamba. Predictive biomarkers of response to immune checkpoint inhibitors in metastatic renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3308.
Abstract 4500: Enedione derivates as a potential cancer treatment through the inhibition of COPZ1
Authors: Allana C. Martins, Barbara Mitsuyasu Barbosa, Ingridhy O. Maia Freitas da Silveira, Roberto Gomes
Journal: Cancer Research (2023)

Abstract Cancer is a leading cause of death worldwide; it was responsible for approximately 10 million deaths in 2020. Besides surgery for tumor removal, the most common treatments available are chemotherapy and radiation, which are not selective, resulting in side effects such as pain, hair loss, nausea, and vomiting. They are also ineffective against stem-like and dormant tumor cells, which could lead to a relapse and/or metastasis. Consequently, the development of drugs with tumor-specific targets is needed. COPI is a coatomer responsible for the retrograde transport from Golgi complex (GC) to the endoplasmic reticulum (ER). In this context, we developed four compounds targeting disruption of GC through inhibition of COPI and previous results showed that compounds 1-4 significantly decrease cell viability of pancreatic cancer cell lines MIA PaCa-2 and AsPC-1, compared to hTERT-HPNE normal pancreatic cell line. In the present work, RT q-PCR confirmed that the two isoforms of the COPI ζ subunit COPZ1 and COPZ2 are expressed at similar levels in normal cells while COPZ2 is downregulated in tumor cell lines. Our in vitro results demonstrated that compounds 1-4 decreased cell viability of breast cancer (HCC1143) and melanoma (A-395) cell lines. The tested compounds are able to target COPZ1-dependent tumor cells, therefore they are great candidates for further studies aiming to develop a selective treatment for cancer. Citation Format: Allana C. Martins, Barbara Mitsuyasu Barbosa, Ingridhy O. Maia Freitas da Silveira, Roberto Gomes. Enedione derivates as a potential cancer treatment through the inhibition of COPZ1. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4500.
Abstract 3307: A novel targeted RNA sequencing approach for identification of aggressive prostate cancer
Authors: Jacob Fredsøe, Christa Haldrup, Iver Nordentoft, Benedicte Ulhøi, Michael Borre, Karina D. Sørensen
Journal: Cancer Research (2023)

Abstract Introduction: Prostate cancer (PC) is a highly heterogeneous disease and can be either aggressive, requiring immediate treatment, or remain slow growing and even without treatment present no significant symptoms throughout the man’s life. Currently, there is an unmet need for new tools that can clearly distinguish indolent from aggressive PC in order to guide treatment decisions.PC is a highly heritable disease and so far, approximately 450 genomic regions associated with PC risk have been defined in genome-wide association studies. Most of these regions are however devoid of annotated genes and consequently the underlying mechanisms behind the associations are not easily elucidated. Accordingly, yet uncharacterized genes in PC-associated regions could be involved in PC development/progression. Methods: We quantified gene expression levels by Kallisto on total RNAseq data from fresh frozen prostate tissue samples from 134 localized PCs, 33 matched adjacent normal (AN) areas as well as 15 PC cell lines. Furthermore, we performed targeted RNAseq covering approximately seven million base pairs divided among 101 PC-risk associated regions (GWAS hits) for in-depth transcriptomic analyses in the same set of samples. HISAT and StringTie were used to identify novel transcripts (genes) with the criteria that a given gene had to have at least 10 reads in more than 50% of all samples to be included. Patient genotyping was performed on Illumina’s global screening array. Results: In totalRNA seq data we observed significant dysregulation of 10,256 genes (5,685 up- and 4,571 downregulated) between AN and localized PC, including upregulation of know PC-associated genes such as SIM2, PCAT7, TDRD1, and TFF3. Interestingly, we found a correlation between high transcription of TFF3 and high risk of biochemical recurrence (BCR) after radical prostatectomy and furthermore a trans-acting eQTL, the PC-risk associated SNP rs1938781. Here, heterozygote patients with the risk-allele had higher risk of BCR than patients homozygous for the reference allele, indicating a potential functional relationship between the PC risk-SNP and TFF3. Additionally, we detected 207 previously unannotated non-coding genes in the capture RNAseq data, where 148 (71.5%) were undetectable in the matched total RNAseq data indicating the existence of stably albeit lowly expressed genes in the genomic areas containing PC-risk SNPs. Citation Format: Jacob Fredsøe, Christa Haldrup, Iver Nordentoft, Benedicte Ulhøi, Michael Borre, Karina D. Sørensen. A novel targeted RNA sequencing approach for identification of aggressive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3307.
Abstract 3304: Immune repertoire sequencing enables accurate clonality determination
Authors: Chen Song, Ariel Erijman, Sean Lund, Bradley W. Langhorst, Pingfang Liu
Journal: Cancer Research (2023)

Abstract The study of complex immunological diseases and tumor microenvironments has advanced through recent developments in sequencing of the immune repertoire. Using this approach, the interrogation of disease progression is facilitated through analysis of millions of V(D)J combinations from B cell receptors (BCRs) and T cell receptors (TCRs). One major challenge of immune repertoire sequencing is to accurately capture the structural and sequence complexities of antibodies and TCR genes during both library preparation and bioinformatic analysis. In addition, the lack of standard reference controls makes assessing sequencing accuracy and sensitivity challenging. Here, we present a method for accurate sequencing of full-length immune gene repertoires of B cells and T cells. RNA extracted from peripheral blood mononuclear cells (PBMCs) or tissues were used for reverse transcription, during which unique molecular identifiers (UMIs) were added to discretely barcode each mRNA molecule. BCR- and TCR-specific PCR primers were used to enrich full-length BCR and TCR sequences. We have implemented a data analysis pipeline to assemble the full length BCR/TCR transcripts and to collapse PCR copies of each mRNA fragment into a single consensus sequence using UMIs. UMI incorporation enables the absolute quantification of input RNA molecules and accurate ranking of antibody/TCR clone abundance. Furthermore, we developed an RNA control pool that contains a large dynamic range of BCR and TCR sequences with a variety of V(D)J combinations, which enables sensitivity and accuracy evaluation of BCR and TCR sequencing. Our immune repertoire sequencing approach allows accurate clonal determination for both BCR and TCR. This technique is applicable for various applications including design of antibody chains for in vitro synthesis, investigation of T cell infiltration of tumor microenvironments, and monitoring of minimal residual disease in cancer patients. Citation Format: Chen Song, Ariel Erijman, Sean Lund, Bradley W. Langhorst, Pingfang Liu. Immune repertoire sequencing enables accurate clonality determination [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3304.
Abstract 4469: Disruption of ATG9A-dependent basal autophagy sensitizes cancer cells to innate inflammatory signaling
Authors: Dasun N. Jayatunge, Tsz-Ming Tsang, Colten M. McEwan, Joshua L. Andersen
Journal: Cancer Research (2023)

Abstract Pathogen-derived nucleic acids are recognized by pattern recognition receptors (PRRs), including cGAS and RIG-I, which trigger the innate immune response by activating IRF3-mediated interferon gene expression. In tumors, high levels of chromosomal instability can also lead to DNA fragments leaking into the cytosol to trigger PRR-mediated interferon response, resulting in pro-inflammatory cytokine secretion from the tumor. This could potentially expose tumor cells to immune attack. However, through mechanisms that are not completely understood, tumor cells dampen the interferon response to escape immune recognition. Previous work demonstrated that loss of ATG9A, but not ATG5, increased inflammatory signaling through the STING-IRF3 cascade, suggesting that perhaps an autophagy-independent function of ATG9A regulates inflammation. Here we found that loss of ATG9A or other upstream regulators of basal autophagy (e.g., ATG101), but not core LC3 lipidation machinery (ATG5 or ATG7), sensitizes cells to dsDNA-induced IRF3 activation and interferon gene expression. We also found that loss of ATG9A or ATG101, but not ATG5 or ATG7, increases the basal activity of the ubiquitin-sensing, IRF3-targeted kinase TBK1, which increases further upon dsDNA treatment. In these ATG9A and ATG101 deficient cells, TBK1 is clustered around large p62-positive condensates that previously been shown to contain large accumulations of LC3. Our preliminary data suggest a model in which ATG9A deletion causes the accumulation of LC3-positive membrane at p62 condensates, which may act as a platform for inflammatory signaling. Our current work focuses on identifying the upstream pathways and core mechanism that regulates IRF3 activation in ATG9A-deficient cells and exploiting this mechanism to improve anti-tumor immunity. Citation Format: Dasun N. Jayatunge, Tsz-Ming Tsang, Colten M. McEwan, Joshua L. Andersen. Disruption of ATG9A-dependent basal autophagy sensitizes cancer cells to innate inflammatory signaling. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4469.
Abstract 3315: Evaluating biomarker potential of germline genomic factors for predicting clinical outcomes in prostate cancer
Authors: Nicole Zeltser, Kathleen E. Houlahan, Sarah M. Al-Hiyari, Stefan E. Eng, Yash Patel, Takafumi N. Yamaguchi, Shu Tao, Rong Rong Huang, Robert E. Reiter, Huihui Ye, Adam S. Kinnaird, Paul C. Boutros
Journal: Cancer Research (2023)

Abstract Prostate cancer is the second-most diagnosed cancer and the second leading cause of cancer death in American men. Early detection is common, but is followed by the more challenging task of prognosing a highly variable clinical course. Current clinical risk-assessment strategies such as serum abundance of prostate specific antigen (PSA), tumor size &amp; extent, and tumor grade based on biopsy are highly imprecise: over a third of patients are over-treated. An improved method of risk stratification may lie in hereditary factors. Prostate cancer is one of the most strongly inherited (h2 = 57%), with accumulating evidence associating rare variants, common variants, and genetic ancestry to clinical outcomes. We have performed germline sequencing on blood from thousands of patients diagnosed with localized prostate cancer and with extensive follow-up data. We quantify the interactions of rare and common variants, and demonstrate that germline features provide insights into patient outcomes and optimal management strategies. Citation Format: Nicole Zeltser, Kathleen E. Houlahan, Sarah M. Al-Hiyari, Stefan E. Eng, Yash Patel, Takafumi N. Yamaguchi, Shu Tao, Rong Rong Huang, Robert E. Reiter, Huihui Ye, Adam S. Kinnaird, Paul C. Boutros. Evaluating biomarker potential of germline genomic factors for predicting clinical outcomes in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3315.
Abstract 3174: Integrative analysis of genome-wide DNA replication origins in human cells
Authors: Mengxue Tian, Zhenjia Wang, Chongzhi Zang, Zhangli Su, Etsuko Shibata, Yoshiyuki Shibata, Anindya Dutta
Journal: Cancer Research (2023)

Abstract Dysregulated DNA replication is associated with cancer development. DNA replication initiates from ~50,000 sites in each cell cycle. Genome-wide profiles of replication origins can be generated using various sequencing-based methods following different molecular capture strategies. No previous study has integrated the results from these different experiments to characterize the most reproducible origins or their association with the replication initiation factor, Origin Recognition Complex (ORC), known to be important for origin-specification. We conducted an integrative analysis of 98 human origin profiling datasets from four different techniques including NS-seq, Repli-seq, Rerep-seq and Bubble-seq, and identified a total of 1,460,610 origins in the human genome. Of these, only 0.12% (1,746) were high-confidence “shared origins” that were detected by all four techniques. Compared with all origins, the shared origins have higher GC content and overlap more with gene promoters, CTCF binding sites, transcription factor (TF) binding hotspots, G-quadruplex sites and activating histone marks. Only ~20% of the shared origins (343) overlap with known ORC binding sites. Despite the low overlap between shared origins and ORC binding sites, permutation tests suggest that the overlap between shared origins, ORC binding sites, R-loops and promoters are all significantly higher than random expectation. The variability in origin identification by different techniques and by same techniques in different groups suggests that replication origins are specified by highly variable stochastic events influenced by epigenetic variability. Citation Format: Mengxue Tian, Zhenjia Wang, Chongzhi Zang, Zhangli Su, Etsuko Shibata, Yoshiyuki Shibata, Anindya Dutta. Integrative analysis of genome-wide DNA replication origins in human cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3174.
Abstract 3176: Modeling the complex multi-cellular ecosystem of the tumor microenvironment in colorectal cancer using multi-omics data
Authors: Geena Ildefonso, Stacey Finley
Journal: Cancer Research (2023)

Abstract The high inter-tumoral phenotypic heterogeneity of colorectal cancer exists within the tumor microenvironment (TME), which ultimately contributes to overall tumor survival. Tumor cells, as the center of the tumor microenvironment, employ sophisticated signaling networks to alter the cell fate decisions between cancerous and non-cancerous cells. A complex network of interactions is the source of this intercellular communication, resulting in tumor growth and progression, drug resistance, and ineffective treatment response. Recent experimental developments in colorectal cancer (CRC) have shown that understanding various underlying mechanisms of tumor growth and progression requires an in-depth understanding of the complex interactions between tumor cells and their surrounding microenvironment. Here, we analyze single-cell RNA sequencing data in CRC and construct gene regulatory networks to define interactions and identify cell states within the TME. The gene regulatory networks are incorporated as a multi-cellular ecosystem representing an experiment-based computational model of phenotypic crosstalk within the TME of CRC. The model simulates and predicts the multi-cellular responses to colorectal cancer to probe and identify mechanisms of cell state evolution and decisions resulting from chemo-agents, used to target TME components. This research will further our understanding of the multi-cellular crosstalk underlying the mechanisms within the TME and facilitate the development and optimization of cancer therapies that inhibit tumor growth in CRC. Citation Format: Geena Ildefonso, Stacey Finley. Modeling the complex multi-cellular ecosystem of the tumor microenvironment in colorectal cancer using multi-omics data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3176.
Abstract 3309: Genomic features, evolutionary patterns, and minimal residual disease at surgical margins as novel prognostic/predictive biomarkers in locally advanced rectal cancer
Authors: Li Li, Kewen He, Aijie Li, Yang Xu, Jiaohui Pang, Dianbin Mu, Jie Ma, Hong Ge, Aurian Maleki, Xueting Qin, Xian Zhang, Qiuxiang Ou, HaiMeng Tang, Yang Shao, Jinming Yu, Shuanghu Yuan
Journal: Cancer Research (2023)

Abstract Background: Locally advanced rectal cancers (LARC) are treated with neoadjuvant chemoradiotherapy (nCRT), total mesorectal excision (TME), and adjuvant chemotherapy, and identifying reliable prognostic/predictive biomarkers is currently warranted for LARC. Methods: Comprehensive genomic profiling was performed in 76 LARC patients who received nCRT plus TME. All 76 patients had baseline tissue biopsies, 72 had paired baseline tissue biopsies and surgical tumor samples, and 55 had paired surgical tumor and margin samples. Post-nCRT tumor regression grade (TRG) and post-surgical disease-free survival (DFS) were used to assess treatment outcomes. Results: Baseline KRAS mutation (P=0.022) and MYC amplification (P=0.047) appeared to be independent prognostic factors for nCRT, with KRAS/MYC-mutated patients having higher tumor regression grade (TRG) and lower immune infiltration. Intriguingly, high radiation doses during nCRT were correlated with improved nCRT response in KRAS/MYC-positive patients. Additionally, aberrations in multiple signaling pathways, especially JAK-STAT (P=0.022), were enriched in TRG3 patients after nCRT, implying that they might be resistance mechanisms that impair nCRT efficacy. The post-surgical FBXW7 mutation was significantly associated with shorter disease-free survival (P=0.01), while treatment-induced branched tumor evolutionary pattern and the molecular level of residual tumor at the surgical margin were significantly correlated with both poorer nCRT response and higher post-surgical recurrence risk. Conclusions: Comprehensive genomic profiling helps identify multiple molecular prognostic and/or predictive biomarkers that could predict patients’ clinical outcomes to nCRT and TME and direct nCRT treatment regimen, thus facilitating more accurate prognostic estimation, a better balance between treatment efficacy and quality of life, and timely adjusted treatment decisions. Citation Format: Li Li, Kewen He, Aijie Li, Yang Xu, Jiaohui Pang, Dianbin Mu, Jie Ma, Hong Ge, Aurian Maleki, Xueting Qin, Xian Zhang, Qiuxiang Ou, HaiMeng Tang, Yang Shao, Jinming Yu, Shuanghu Yuan. Genomic features, evolutionary patterns, and minimal residual disease at surgical margins as novel prognostic/predictive biomarkers in locally advanced rectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3309.